The objective of this project is to determine how inflammatory signaling by Toll-like receptor-2 (TLR2) and TLR4 regulate depression-like behaviors in mice to develop new therapeutic targets for major depression. This exciting possibility is based on our novel Preliminary Results showing that TLR4 signaling increases susceptibility to depression onset modeled in mice, whereas TLR2 signaling promotes recovery from depression. These balancing mood-regulating actions of inflammatory receptors typifies the immune system characteristic of balancing signals in order to respond to damage or infection, but limiting the response to avoid damage to the host. This is an important subject because major depression is highly prevalent and debilitating in veterans, and therapies are often not adequate. Novel targets need to be identified to develop new therapies, and the inflammatory system is one such novel target, as substantial evidence demonstrates inflammatory activation promotes depression. We also propose that drug development may have been limited by a primary focus on modulating onset in animal models, whereas recovery from depression is equally important for therapy development. By giving equal weight to examining susceptibility and recovery and examining receptors that mediate inflammatory signaling, our Preliminary Results demonstrate that TLR4 promotes onset and TLR2 provides the balance by promoting recovery from depression. Our overall hypothesis is that TLR-mediated signals regulate maintenance of mood homeostasis, whereas abnormalities in TLR actions promote the development and prolongation of depression. Testing this hypothesis will establish the potential for drugs acting on TLR2 and TLR4 to bolster resistance to depression and support recovery. Specific Aim 1 will test the hypothesis that TLR2 and TLR4 oppositely regulate depression-like behavior in mice. A panel of behavioral assessments widely used to model depression-like behaviors will be applied to TLR2 and TLR4 knockout mice, with and without antidepressant treatment, examining both onset and recovery. Specific Aim 2 will test behavioral outcomes of pharmacologically modulating TLR2 and TLR4. We will test the hypothesis that TLR2 agonists and TLR4 antagonists are antidepressant. Specific Aim 3 will test mechanisms that regulate recovery from depressive-like behavior. We will test mechanisms that regulate signaling involved in recovery from depression, such as cytokines and brain-derived neurotrophic factor (BDNF), and examine proteins reported to be involved in mood regulation, to identify those critical for the pro-depressant effect of TLR4 stimulation and depression-recovery facilitating effect of TLR2 stimulation. Altogether this is an innovative project examining TLR2/4 as feasible therapeutic targets to reduce the susceptibility and duration of depression modeled in mice, an important problem affecting the health of many veterans.